Interrogating host immunity to predict treatment response in inflammatory bowel disease

Abstract

IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy. IBD treatment has an expanding repertoire of drugs targeting different aspects of the immune response. This Review focuses on unravelling the complexity of mucosal immune responses in IBD pathogenesis and how analytical assays might be harnessed to effectively stratify and individualise IBD therapy. IBD has a growing repertoire of treatments targeting different aspects of the immune response but all treatments are hampered by primary and secondary loss of response. Tofacitinib, a JAK inhibitor, is licensed for the treatment of ulcerative colitis, and other selective JAK inhibitors and IL-23p19 inhibitors are in phase III trials and expected to change treatment paradigms in IBD. Precision medicine is highly desirable to fast-track patients to the most appropriate therapy at the earliest opportunity, thereby reducing complications of chronic inflammation and limiting corticosteroid exposure. Biological insights into disease pathogenesis have unveiled different targets that might serve to predict outcomes in IBD, and the identification of laboratory assays with clinical utility is now a pressing priority for biomarker development. Promising platforms to deliver precision medicine approaches in IBD include in vivo molecular endoscopy, transcriptomics, germline genetics, gut microbiome analysis and profiling of the immune response.